Human immunodeficiency virus type 1 (HIV-1) genetic variation is high among virus populations and is of importance clinically for both drug resistance and vaccine development. A high rate of HIV mutation along with a high turnover rate of infected cells drives virus variation. This viral variation is thought to be responsible for the gradual breakdown of the immune system and is the mechanism of disease progression to AIDS. In the current application, we seek funding to continue studies began over a decade ago. We propose to examine the role of HIV mutation and its role on shaping replication capacity. We also propose to investigate these aspects of HIV-1 replication by analysis of reverse transcriptase mutants that alter virus variation relative to that of wt virus. We will explore how adaptive mutations can impact HIV-1 variation during the selection of new virus variants. We will determine whether the adaptive selection for altered replication capacity results in the selection of variant viruses. Lastly, we will investigate the origins of mutations in HIV-1 proviruses to determine mechanisms of virus variability.